Hindawi Publishing Corporation Case Reports in Pediatrics Volume 2013, Article ID 284029, 3 pages http://dx.doi.org/10.1155/2013/284029

Case Report An Unusual Case of Rapidly Progressive Hyperbilirubinemia

Kimberly M. Thornton,1,2 Michael F. Nyp,1,2 Lejla Music Aplenc,2,3 Gary L. Jones,2,4 Shannon L. Carpenter,2,4 Erin M. Guest,2,4 Steven M. Shapiro,2,5 and Winston M. Manimtim1,2

1 Division of Neonatology-Perinatology, Children’s Mercy Hospitals and Clinics, 2401 Gillham Road, Kansas City, MO 64108, USA 2 School of Medicine, University of Missouri-Kansas City, 2411 Holmes Road, Kansas City, MO 64108, USA 3 Division of Pathology, Children’s Mercy Hospitals and Clinics, 2401 Gillham Road, Kansas City, MO 64108, USA 4 Division of Hematology-Oncology, Children’s Mercy Hospitals and Clinics, 2401 Gillham Road, Kansas City, MO 64108, USA 5 Division of Neurology, Children’s Mercy Hospitals and Clinics, 2401 Gillham Road, Kansas City, MO 64108, USA

Correspondence should be addressed to Winston M. Manimtim; [email protected]

Received 7 August 2013; Accepted 17 September 2013

Academic Editors: A. M. Das, A. Mohta, M. Pineda, and D. I. Zafeiriou

Copyright © 2013 Kimberly M. Thornton et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

We present an unusual case of hyperbilirubinemia with rapid early progression leading to bilirubin encephalopathy in a term neonate. Despite early recognition and intervention, the total serum bilirubin reached a maximum level of 39 mg/dL at 32 hours of life. Prior to an emergent exchange transfusion, the patient’s diagnostic evaluation was significant for Coombs-negative microangiopathic hemolytic anemia and thrombocytopenia. Further testing revealed a deficiency of ADAMTS13 protein, or von Willebrand factor-cleaving protease, a finding diagnostic of congenital thrombotic thrombocytopenic purpura, or Upshaw- Schulman syndrome. This rare disease is often misdiagnosed, especially in the newborn period.

1. Introduction age,theinfantwasnotedtohaveahematomaathisvitamin K intramuscular injection site. He developed jaundice at <24 Hyperbilirubinemia is one of the most common reasons for hours of age, with a total serum bilirubin (TSB) of 33.3 mg/dL admissiontoanintensivecarenursery.Despiteasystematic at 29 hours of age. High intensity phototherapy was promptly approach towards prevention, bilirubin encephalopathy still initiated and he was transferred to a level III neonatal occurs and remains as a neonatal emergency requiring early intensive care unit. intervention to prevent permanent neurologic sequelae. Here Laboratory evaluation revealed infant blood type O+, we report an atypical presentation of bilirubin encephalopa- negative direct antibody test, mild anemia (hemoglobin thy due to congenital thrombotic thrombocytopenic purpura 11.6 gm/dL), thrombocytopenia (26,000), elevated serum (TTP). creatinine (1.3 mg/dL), elevated aspartate aminotransferase (248 units/L), and elevated reticulocyte count (4.9%). All 2. Case Presentation other labs were within normal limits, including the white blood cell count and coagulation studies (prothrombin time, A 40-week gestation, 3.1 kg, Hispanic male infant was born partial thromboplastin time, and fibrinogen). The TSB was via spontaneous vaginal delivery to a 22-year-old gravida 4 eventually as high as 39 mg/dL at 32 hours of life. On physical para 3 spontaneous abortion 1 mother without significant past exam, he was markedly jaundiced, irritable, and hypertonic. medical history. Maternal blood type was O+ and antibody He was also noted to have a high-pitched cry and intermit- screen was negative. Other maternal prenatal labs were unre- tent opisthotonic posturing. At 35 hours of age, he under- markable. There was no known history of jaundice, anemia, went double-volume exchange transfusion with reconstituted or hematologic disorders in family members. Apgar scores packed RBCs. After-exchange, the TSB was 23.3 mg/dL and were 7 and 8 at 1 and 5 minutes, respectively. At 4 hours of declined steadily thereafterFigure ( 1). 2 Case Reports in Pediatrics

45 40 Arrival to tertiary care and start of phototherapy

35 Postexchange transfusion 30 Post-IVIG Schistocyte 25 Clinical seizures and intubation 20 15 Extubation 10 Abnormal brain MRI Total bilirubin (mg/dL) bilirubin Total 5 0 0 50 100 150 200 250 Age (hours) Figure 2: The patient’s peripheral blood smear showing microan- Figure 1: Graph of the patient’s total bilirubin values (mg/dL) and giopathic hemolytic anemia. age (hours) with pertinent clinical events.

Following the exchange transfusion, he developed symp- accumulate, leading to the formation of platelet-rich intravas- toms of encephalopathy including seizures and persistent cular microthrombi [2]. These micro-thrombi, in turn, cause apnea requiring mechanical ventilation for two days. EEG damagetocirculatingredbloodcellsaswellasischemiato confirmed multifocal seizures and diffuse encephalopathy. vital organs. BrainMRIat8daysshowedT1-weightedhyperintensityof Acquired TTP, the more common form, is usually the globus pallidus. Peripheral blood smear showed microan- an autoimmune disease caused by antibodies against giopathic hemolysis, suggestive of TTP among other diag- ADAMTS13 protein. The rare congenital form of disease, noses (Figure 2). The ADAMTS13 (a disintegrin and metallo- also known as Upshaw-Schulman syndrome, is caused by a proteinase with a thrombospondin type 1 motif, member 13) mutation of the gene coding for ADAMTS13 found on chro- enzymatic activity was measured using the FRETS-VWF73 mosome 9q34 and follows an autosomal recessive pattern of substrate, a synthetic 73-amino-acid peptide. Cleavage of the inheritance [3]. The mutation results in a deficiency of the substrate by ADAMTS13 causes it to fluoresce over time, protein itself or a decrease in the functionality of the protein. with patients deficient in the ADAMTS13 enzyme showing a Unlike cases of immune-mediated hemolysis, congenital TTP decrease in fluorescence compared with controls. Our patient may be treated with transfusions of fresh frozen plasma to was confirmed to be deficient in an enzyme activity of <5%. replace the missing protein. Gene sequencing analysis showed a heterozygous missense Multiple gene mutations are associated with severe defi- mutation in the ADAMTS13 gene [c.304C>T(p.Arg102Cys)]. ciency of ADAMTS13 activity, and the cause of variable phe- Because hyperbilirubinemia can interfere with the notypic expression is not yet understood [4]. Very few cases of FRETS-VWF73 substrate assay, the ADAMTS13 level was congenital TTP have been recognized during the newborn repeatedataround5monthsofage,whenthechildwasnotin period, and, upon review of cases diagnosed in later child- an acute hemolytic state. Results of the testing again showed hood, some had a history of severe hyperbilirubinemia after an enzyme activity level of <5%. At 8 months, he had auditory birth requiring double-volume exchange transfusion [2, 4, 5]. predominant kernicterus [1], mild truncal hypotonia, and The classic symptoms of chronic bilirubin encephalopa- impaired upward gaze. His sensorimotor development was thy, or kernicterus, include dystonic or athetoid cerebral otherwise normal for age. Diagnostic auditory testing at the palsy, auditory neuropathy spectrum disorder with or with- time revealed a severe auditory neuropathy spectrum disor- out hearing loss, impaired upward gaze, and tooth enamel der. The patient’s neurologic deficits have improved over time, dysplasia [1]. Brain MRI shows hyperintensity of the globus but he continues to have significant hearing loss. He receives pallidus and, possibly, subthalamic nuclei on T1-weighted regular prophylactic FFP infusions and is being considered imaging when performed in the first weeks after birth, with for cochlear implants. hyperintensity in these areas on T2-weighted imaging per- formed later [1]. 3. Discussion Our patient’s brain MRI findings are more consistent with bilirubin toxicity rather than a microvascular ischemic event, TTP is a disease in which microthrombi form in multiple which could also be present in a child with congenital TTP. small vessels throughout the body leading to signs and symp- Our patient’s genetic testing has only revealed a heterozygous toms of organ ischemia. The normal coagulation process mutation of the ADAMTS13 gene, but it is postulated that involves von Willebrand factor (vWF), a large multimeric the other chromosome either has a mutation in a noncoding protein which binds platelets to areas of intravascular endo- region or a mutation affecting protein processing that has yet thelial cell damage. In normal hemostasis, the function of to be identified. There have been other cases reported inthe ADAMTS13 protease is to cleave vWF multimers [2]. When literature with significant disease and only one allele affected ADAMTS13 activity is deficient, ultra-large vWF multimers [2]. It is important to note that while genetic testing can be Case Reports in Pediatrics 3 informative, low ADAMTS13 activity is considered diagnos- tic of congenital TTP. In conclusion, congenital TTP is a rare disease but should be considered in any case of hyperbilirubinemia occurring in conjunction with thrombocytopenia and hemolytic anemia. This case points out the importance of obtaining a peripheral smear in cases of strikingly high TSB levels.

Conflict of Interests The authors declare no conflict of interests.

References

[1] S. M. Shapiro, “Chronic bilirubin encephalopathy: diagnosis and outcome,” Seminars in Fetal and Neonatal Medicine,vol.15, no. 3, pp. 157–163, 2010. [2]L.A.Lotta,I.Garagiola,R.Palla,A.Cairo,andF.Peyvandi, “ADAMTS13 mutations and polymorphisms in congenital thrombotic thrombocytopenic purpura,” Human Mutation,vol. 31,no.1,pp.11–19,2010. [3] G. G. Levy, W. C. Nichols, E. C. Lian et al., “Mutations in a member of the ADAMTS gene family cause thrombotic throm- bocytopenic purpura,” Nature, vol. 413, no. 6855, pp. 488–494, 2001. [4] Y. Fujimura, M. Matsumoto, A. Isonishi et al., “Natural history of Upshaw-Schulman syndrome based on ADAMTS13 gene analysis in Japan,” Journal of Thrombosis and Haemostasis,vol.9, supplement 1, pp. 283–301, 2011. [5] D.E.Schiff,W.D.Roberts,J.Willert,andH.M.Tsai,“Thrombo- cytopenia and severe hyperbilirubinemia in the neonatal period secondary to congenital thrombotic thrombocytopenic pur- pura and ADAMTS13 deficiency,” Journal of Pediatric Hematol- ogy/Oncology,vol.26,no.8,pp.535–538,2004. M EDIATORSof INFLAMMATION

The Scientific Gastroenterology Journal of Research and Practice Diabetes Research Disease Markers World Journal Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

Journal of International Journal of Immunology Research Endocrinology Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

Submit your manuscripts at http://www.hindawi.com

BioMed PPAR Research Research International Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

Journal of Obesity

Evidence-Based Journal of Stem Cells Complementary and Journal of Ophthalmology International Alternative Medicine Oncology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

Parkinson’s Disease

Computational and Mathematical Methods Behavioural AIDS Oxidative Medicine and in Medicine Neurology Research and Treatment Cellular Longevity Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014